The induction of cancers from the epithelia of the different segments of the respiratory tract in animal models by multifactorial mechanisms is studied by treatments with combinations of chemical, physical and biological factors. Age at beginning of treatment is an important factor in the induction of respiratory tumors by diethylnitrosamine in a segment-specific manner. In hamsters treated from birth, there is an increased incidence and decreased latency of nasal cancers, in comparison with hamsters started at 8 weeks of age; no significant age-related effect was found on the induction of tracheal or lung neoplasms. Concurrent intraperitoneal injection of dimethylsulfoxide increased the incidence and severity and decreased the latency of respiratory tumors induced by intratracheal administation of suspensions of benzo[a]pyrene (BP) combined with ferrix oxide. A complex multifactorial experiment of respiratory carcinogenesis in hamsters has been completed and the results are under analysis; preliminary results show that a single dose of N-methyl-N-nitrosourea (MNU) 2 weeks prior to a series of BP/ferric oxide administrations markedly enhances laryngeal and bronchial carcinogenesis relative to exposure to either carcinogen alone. Localized injury to the trachea enhances the carcinogenic effect of BP/ferric oxide not only in the trachea, but also in the bronchi. Previous exposure to BP/ferric oxide increases DNA binding of BP in all exposed slegments of the respiratory tract, with the trachea showing the highest and the most transient binding levels. Silica-induced pulmonary epithelial proliferative lesions are studied for their pathogenetic relationship to granulomatous cell reaction and to cellular mediators of inflammation, in conjunction with long-term carcinogenesis studies of different forms of silica (quarta, cristobalite, tridymite).